DNA replication
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UCLA symposia on molecular and cellular biology ; New series //Vol. 47
782 s. : il.
- MeSH
- rekombinace genetická MeSH
- replikace DNA MeSH
- Publikační typ
- kongresy MeSH
- Konspekt
- Biologické vědy
- NLK Obory
- biologie
- embryologie a teratologie
- genetika, lékařská genetika
1st ed. XXII, 493 s. : fot., obr., rejstř., přeruš.lit. ; 26 cm
Cold spring harbor monograph series ; Monograph 31
[1st ed.] xiii, 1058 s. : il.
- MeSH
- DNA MeSH
- eukaryotické buňky MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- biologie
- biochemie
- MeSH
- DNA virů biosyntéza MeSH
- kuřecí embryo MeSH
- replikace viru MeSH
- virus vakcinie MeSH
- Check Tag
- kuřecí embryo MeSH
- MeSH
- cytopatogenní efekt virový MeSH
- cytoplazma MeSH
- DNA biosyntéza MeSH
- replikace viru MeSH
- Publikační typ
- přehledy MeSH
Poly(ADP-ribose) polymerase 1 (PARP1) is implicated in the detection and processing of unligated Okazaki fragments and other DNA replication intermediates, highlighting such structures as potential sources of genome breakage induced by PARP inhibition. Here, we show that PARP1 activity is greatly elevated in chicken and human S phase cells in which FEN1 nuclease is genetically deleted and is highest behind DNA replication forks. PARP inhibitor reduces the integrity of nascent DNA strands in both wild-type chicken and human cells during DNA replication, and does so in FEN1-/- cells to an even greater extent that can be detected as postreplicative single-strand nicks or gaps. Collectively, these data show that PARP inhibitors impede the maturation of nascent DNA strands during DNA replication, and implicate unligated Okazaki fragments and other nascent strand discontinuities in the cytotoxicity of these compounds.
DNA synthesis of the leading and lagging strands works independently and cells tolerate single-stranded DNA generated during strand uncoupling if it is protected by RPA molecules. Natural alkaloid emetine is used as a specific inhibitor of lagging strand synthesis, uncoupling leading and lagging strand replication. Here, by analysis of lagging strand synthesis inhibitors, we show that despite emetine completely inhibiting DNA replication: it does not induce the generation of single-stranded DNA and chromatin-bound RPA32 (CB-RPA32). In line with this, emetine does not activate the replication checkpoint nor DNA damage response. Emetine is also an inhibitor of proteosynthesis and ongoing proteosynthesis is essential for the accurate replication of DNA. Mechanistically, we demonstrate that the acute block of proteosynthesis by emetine temporally precedes its effects on DNA replication. Thus, our results are consistent with the hypothesis that emetine affects DNA replication by proteosynthesis inhibition. Emetine and mild POLA1 inhibition prevent S-phase poly(ADP-ribosyl)ation. Collectively, our study reveals that emetine is not a specific lagging strand synthesis inhibitor with implications for its use in molecular biology.
